This invention relates to preparation of adhesive compositions. More particularly, the invention relates to preparation of hydrophilic pressure sensitive adhesive (PSA) compositions having optimized adhesive properties and that are useful, for example, in transdermal drug delivery systems and other medical, pharmaceutical and cosmetic products that adhere to the skin or other body surface. The invention has utility in a number of fields, including transdermal drug delivery, iontophoretic systems, biomedical electrode fabrication, wound healing, and skin care and cosmetic products.
Pressure-sensitive adhesives are well known and have been used for many years in a variety of industrial, consumer and medical applications. Pressure-sensitive adhesives are characterized as being normally tacky and exhibiting instant tack when applied to a substrate. Many polymers have been used to manufacture pressure sensitive adhesives as, for example, acrylic and methacrylic ester homo- or copolymers, butyl rubber-based systems, silicones, urethanes, vinyl esters and amides, olefin copolymer materials, natural or synthetic rubbers, and the like. All the PSAs are elastomers, i.e. they exhibit viscoelastic properties typical of rubbers.
Pressure sensitive adhesives are used extensively in transdermal drug delivery devices, or xe2x80x9cpatches,xe2x80x9d that adhere to the skin or mucosal tissue during use. Adhesive, transport, reservoir and biological properties of polymeric composites constitute a basis for their application in transdermal drug delivery systems, as follows:
Adhesive: High tack coupled with an optimum slip-stick transition point.
Transport: Drug release kinetics controlled in terms of transdermal delivery rate and the functional lifetime of device.
Reservoir: Drug compatibility and ability to be stored in a stable form tailored to the incorporated drug of interest.
Biological: No toxicity, skin irritation and sensitization.
Such diverse requirements are difficult to combine in a single system.
Examples of pressure sensitive adhesives that have been proposed for use in transdermal drug delivery systems include polysiloxanes (e.g., polydimethyl siloxanes, polydiphenyl siloxanes, and siloxane blends), polyisobutylenes, polyacrylates, acrylic acid-acrylate copolymers (e.g., copolymers of acrylic acid copolymers with 2-ethylhexyl acrylate or isooctyl acrylate), and tacky rubbers such as polyisobutene, polybutadiene, polystyrene-isoprene copolymers, polystyrene-butadiene copolymers, and neoprene (polychloroprene). All of these PSAs are hydrophobic polymers and their common disadvantage is a loss in adhesion toward hydrated substrates.
xe2x80x9cBioadhesionxe2x80x9d is defined as a pressure sensitive adhesion with respect to highly hydrated biological tissues such as mucosal tissue. In contrast to conventional PSAs (rubber, polysiloxanes and acrylates) that adhere mainly to dry substrates, bioadhesives (BAs) exhibit good tack when adhered to hydrated biological substrates. To be bioadhesive, water should provide a plasticizing effect on a polymer, i.e., the polymer should be hydrophilic. For example, the range of typical BAs includes slightly cross-linked polyacrylic and polymethacrylic acids (EP 0371 421) as well as blends of hydrophilic cellulose derivatives (40-95%) with polyethylene glycol (PEG) (U.S. Pat. No. 4,713,243).
Bioadhesives become tacky as the crosslinked polymer swells in significant quantities of water. The cohesive strength of highly swollen hydrophilic polymers is generally low and the BAs thus differ from the PSAs in this regard.
For a number of practical purposes, it can be highly useful to have a range of PSA and BA polymeric materials of different hydrophilicity and thus different solubilities in water or in the liquids secreted by the skin and mucosa (sweat, mucus, saliva etc.). Attempts to combine the properties of PSAs and BAs have been described by Biegajski et al. in U.S. Pat. No. 5,700,478, where a water-soluble pressure-sensitive mucoadhesive was obtained by blending of 95-40% polyvinylpyrrolidone (PVP) with 0-50% hydroxypropyl cellulose (HPC) and 11-60% glycerol. Other examples of hydrophilic polymer blends coupling the properties of PSAs and BAs involve polyacrylic acid-polyvinyl alcohol (PAA-PVA) interpolymeric complexes formed by hydrogen bonding between the monomer units of the complementary polymers chains and plasticized with PEG-200, glycerol or polypropylene glycol (PPG), molecular weight 425 g/mol (German Patent Application DE 42 19 368).
The ideal performance characteristics of an adhesive intended for use on human skin and/or mucosal tissue present difficult and conflicting technical requirements. Initially, of course, the pressure sensitive adhesive should be suitable for long-term skin contact, and permeable to and physically and chemically compatible with the active agent and any permeation enhancers or other vehicles or additives that are present. The ideal adhesive should also be nonirritating, noncomedogenic and nonsensitizing, yet bond quickly to skin or mucosal tissue at the intended site of use with only very slight pressure. The adhesive should maintain its bond for as long a period of time as necessary and be resistant to inadvertent removal, yet be easily removed without removing any skin or leaving a residue (a suitable strength of an adhesive joint with the skin ranges from about 200 to 400 N/m under the 180 degree peel test). High tack (i.e., greater than about 50 g/cm2) should be coupled with an optimum transition point from adhesive to cohesive failure. Furthermore, the adhesive should not be weakened or destroyed by exposure to moisture or high humidity. Finally, in order to protect a wound or maintain the integrity of placement of an electrode or other device, the adhesive should resist skin movement and be able to transfer a mechanical load from the adhesive backing to the skin.
For many pharmaceuticals, the solubility of the active agent in the reservoir of a transdermal drug delivery device is of decisive importance. With higher solubility, it is possible to increase the rate of transdermal delivery (i.e., the rate at which the active agent migrates from the device and into the skin or mucosal tissue). Because many therapeutic agents are ionogenic organic substances having a higher solubility in hydrophilic media than in lipophilic media, adhesive reservoirs based on hydrophilic polymers would be more versatile than adhesive reservoirs based on hydrophobic polymers. Furthermore, as noted above, pressure sensitive adhesives for application to mucosal tissue should adhere well to hydrated substrates, and hydrophilic adhesives would therefore be ideal.
General advantages of hydrophilic adhesives are as follows:
1. Hydrophilic adhesives can provide greater adhesion compared with hydrophobic adhesives, because the surface energy of hydrophilic adhesives is typically higher and closer to that of biological substrates such as skin and mucosal membranes.
2. Hydrophilic adhesives are compatible with a wide variety of drugs, excipients and additives.
3. The plasticizing effect of water sorbed by hydrophilic adhesives from hydrated skin or mucosal tissues enhances adhesion, in contrast to hydrophobic adhesives.
4. The enhanced solubility of drugs in hydrophilic adhesives facilitates control over drug release kinetics.
5. With hydrophilic adhesives, based on hydrophilic polymers, there is an expanded capability to control and manipulate the adhesive-cohesive balance.
6. The adhesive properties of hydrophilic polymers are considerably less sensitive to their molecular weight than those of hydrophobic polymers, as a result of specific intramolecular and intermolecular interaction within hydrophilic adhesives.
In order to increase the hydrophilicity of an adhesive composition, hydrophobic PSAs have been xe2x80x9chydrophilizedxe2x80x9d by incorporation of non-tacky hydrophilic polymers and fillers into a hydrophobic adhesive. Thus, polyisobutylene (PIB) PSA has been hydrophilized by incorporation of cellulose and cellulose derivatives (U.S. Pat. No. 4,231,369), polyvinyl alcohol (PVA), pectin and gelatin (U.S. Pat. Nos. 4,367,732 and 4,867,748), and SiO2 (U.S. Pat. No. 5,643,187). Rubber adhesives have also been modified by filling with amphiphilic surfactants, or by treating the PSA polymer with a plasma-oxygen discharge. Acrylic PSAs can be hydrophilized by incorporation of PVP (U.S. Pat. No. 5,645,855). Hydrophilization of hydrophobic adhesives, while somewhat effective, tends to result in a partial loss of adhesion.
Accordingly, there is a need in the art for a novel hydrophilic adhesive composition suitable for use in a wide variety of contexts, e.g., in a topically applied drug delivery system, which composition meets all of the above criteria and provides for an effective delivery rate of any active agent, whether hydrophilic, ionogenic, or lipophilic in nature.
The present invention is addressed to the aforementioned need in the art, and enables the development of a wide range of hydrophilic pressure-sensitive adhesives that not only meet all of the aforementioned criteria but provide other advantages as well. For example, the adhesive compositions combine the properties of pressure-sensitive adhesives and bioadhesives and can be used in a number of contexts, including not only transdermal, transmucosal and topical drug delivery systems but also in wound healing products, biomedical electrodes, iontophoretic systems, bioadhesive cushions, and the like. Also, the adhesive compositions can be used with a number of active agents, regardless of hydrophilicity, hydrophobicity, and molecular structure. Manufacture of adhesive products using the present compositions is readily accomplished by a simple extrusion process, obviating the need for organic solvents and the conventional, time-consuming blending and casting method. Finally, the adhesive composition may be readily tailored during manufacture with respect to hygroscopicity, the desired degree of hydrophilicity, adhesive and cohesive strength, and drug delivery kinetics.
It is thus a primary object to address the above-described need in the art by providing a method for making hydrophilic pressure sensitive adhesive compositions useful in transdermal drug delivery systems, iontophoretic systems, wound healing products, biomedical electrodes, and other devices and systems requiring a bioadhesive.
It is another object of the invention to provide a hydrophilic pressure sensitive adhesive that is optimized with respect to adhesive strength, cohesive strength and hydrophilicity.
It is another object of the invention to provide a therapeutic system for the topical or transdermal administration of a pharmacologically active agent, wherein the system is provided with an adhesive means comprised of a hydrophilic pressure sensitive adhesive composition as provided herein.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect of the invention, then, a method is provided for preparing an adhesive composition having an optimized degree of adhesion, comprising:
(a) preparing a plurality of compositions each comprised of a hydrophilic polymer having a glass transition temperature Tg pol admixed with a plasticizer having a glass transition temperature Tg pl and capable of covalently or noncovalently crosslinking the hydrophilic polymer, wherein the weight fraction of the hydrophilic polymer in each composition is wpol, and the weight fraction of the plasticizer in each composition is wpl;
(b) calculating predicted glass temperatures Tg predicted for each composition using the Fox equation (1)                               1                      T                          g              ⁢                              xe2x80x83                            ⁢              predicted                                      =                                            w              pol                                      T                              g                pol                                              +                                    w              pl                                      T                              g                pl                                                                        (        1        )            
and plotting Tg predicted versus wpl, for each composition;
(c) determining the glass transition temperature Tg actual for each composition, and plotting Tg actual versus wpl, for each composition;
(d) identifying the region of the plots of (b) and (c) wherein Tg actual is less than Tg predicted; such that there is a negative deviation from Tg predicted;
(e) within the region identified in (d), identifying the optimum weight of plasticizer wpl optimum at which the negative deviation from Tg predicted is at a maximum; and
(f) admixing a monomeric precursor to the hydrophilic polymer and the plasticizer under polymerizing conditions to provide an adhesive composition having an optimized degree of adhesion, wherein the weight fraction of plasticizer in the composition is wpl optimums and the weight fraction of the hydrophilic polymer in the composition is 1-wpl optimum.
In some cases, e.g., when a lower degree of adhesion is desired, the selected weight percent of the plasticizer will not correspond to the maximum negative deviation of Tg actual from Tg predicted, but will correspond to some other predetermined deviation of Tg actual from Tg predicted. Accordingly, in another aspect of the invention, a method is provided for preparing an adhesive composition having a predetermined degree of adhesion, comprising:
(a) preparing a plurality of compositions each comprised of a hydrophilic polymer having a glass transition temperature Tg pol admixed with a plasticizer having a glass transition temperature Tg pl and capable of covalently or noncovalently crosslinking the hydrophilic polymer, wherein the weight fraction of the hydrophilic polymer in each composition is wpol, and the weight fraction of the plasticizer in each composition is wpl, such that wpol is equal to 1-wpl;
(b) calculating predicted glass temperatures Tg predicted for each composition using the Fox equation (1)                               1                      T                          g              ⁢                              xe2x80x83                            ⁢              predicted                                      =                                            w              pol                                      T                              g                pol                                              +                                    w              pl                                      T                              g                pl                                                                        (        1        )            
and plotting Tg predicted versus wpl for each composition;
(c) determining the glass transition temperature Tg actual for each composition, and plotting Tg actual versus wpl for each composition;
(d) identifying the region of the plots of (b) and (c) wherein Tg actual has a predetermined deviation from Tg predicted; and
(e) admixing a monomeric precursor to the hydrophilic polymer and the plasticizer under polymerizing conditions to provide an adhesive composition having a predetermined degree of adhesion, wherein the weight percent of plasticizer in the composition corresponds to a value within the region identified in section (d).
In another aspect of the invention, a hydrophilic pressure sensitive adhesive composition is provided that comprises (1) a hydrophilic polymer having a glass transition temperature Tg pol, and (2) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature Tg pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature Tg actual of the composition from (b) the predicted glass transition temperature Tg predicted calculated for the composition using the Fox equation. For maximum adhesion, the predetermined deviation is the maximum negative deviation of Tg actual from Tg predicted. Preferably, the difference between Tg pol and Tg pl is at least about 50xc2x0 C., such that Tg actual for each composition is determined solely by Tg pl.
In related aspects of the invention, a hydrophilic pressure sensitive adhesive composition is provided that comprises (a) a hydrophilic polymer, and (b) a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the ratio of hydrogen bonding to covalent crosslinks and/or the ratio of the hydrophilic polymer to the plasticizing agent are selected to optimize the hydrophilicity, adhesive strength and cohesive strength of the composition.
In a further aspect of the invention, a drug delivery system is provided for the topical or transdermal administration of a pharmacologically active agent. The drug delivery system includes:
(A) a drug reservoir comprising (1) a substantially nonaqueous pressure sensitive adhesive matrix of a hydrophilic polymer having a glass transition temperature Tg pol, and a complementary hydroxyl-terminated or carboxyl-terminated short-chain plasticizing agent having a glass transition temperature Tg pl and capable of hydrogen bonding or electrostatic bonding to the hydrophilic polymer, wherein the weight ratio of hydrophilic polymer to complementary short-chain plasticizing agent is selected so to provide a predetermined deviation in (a) the actual glass transition temperature Tg actual of the composition from (b) the predicted glass transition temperature Tg predicted for the composition calculated using the Fox equation, and (2) a therapeutically effective amount of the active agent; and
(B) a backing layer laminated to the drug reservoir that serves as the outer surface of the device during use.
The adhesive compositions herein are also useful in a host of additional applications, e.g., in bandages, wound and burn dressings, ostomy devices, prosthesis securing means, face masks, sound, vibration or impact absorbing materials, and the like. The compositions may be rendered electrically conductive by incorporation of water and/or another electrically conductive material, and may thus be used for attaching an electroconductive article, such as an electrode (e.g., a transcutaneous electric nerve stimulation, or xe2x80x9cTENSxe2x80x9d electrode, an electrosurgical return electrode or an EKG monitoring electrode), to an individual""s body surface.